tbuckley/cabot-search huggingface dataset:
Abstract 6183: A novel NQO1 bioactivatable drug induces mitochondrial dysfunction and G2/M phase cell cycle arrest to selectively kill pancreatic cancer cells
Authors: Xiumei Huang, Lingxiang Jiang, Matthew W. Boudreau, Paul J. Hergenrother
Journal: Cancer Research (2022)

Abstract As a fatal disease with short overall survival, pancreatic cancer is among the top five leading cause of cancer-related deaths worldwide, current therapies against pancreatic cancer lack tumor specificity and generally cause toxic side effects on normal and healthy tissues. Thus, exploring and developing novel tumor-specific agents for treating pancreatic cancer is a critical need. NAD(P)H:quinone oxidoreductase 1 (NQO1) is elevated in the pancreatic cancers whereas it lacks in associated normal tissues. Therefore, NQO1 bioactivatable drugs are promising due to tumor-selective killing NQO1-positive cancer cells. Our previous studies have revealed that the novel NQO1 bioactivatable drug - deoxynyboquinone (DNQ) is ten-fold more potent than the prototypic NQO1 bioactivatable drug β-lapachone to efficiently kill NQO1-positive cancer cells. However, DNQ causes a severe side effect action - high-grade methemoglobinemia that limits its clinical usefulness. Here, we developed a novel DNQ derivative, isopentyl-deoxynboquinone (IP-DNQ), which selectively killed pancreatic ductal adenocarcinoma (PDA) cells in an NQO1-dependent way with an extremely low IC50 (0.1 µM). IP-DNQ evoked massive ROS production and oxidative DNA lesions, resulting in PARP1 hyperactivation and mitochondrial catastrophe. Furthermore, we also observed that IP-DNQ induced G2/M phase cell cycle arrest and promoted programmed necrosis and caspase-dependent apoptosis co-existing in IP-DNQ-treated NQO1-positive pancreatic cancer cells. In addition, IP-DNQ treatment caused extremely low side effect of methemoglobinemia, significantly suppressed tumor growth and extended mice lifespan in orthotopic pancreatic cancer xenograft model. In summary, our findings offer a novel potential therapy against NQO1-positive pancreatic cancers and enable mechanism-based synergy with other anticancer drugs. Citation Format: Xiumei Huang, Lingxiang Jiang, Matthew W. Boudreau, Paul J. Hergenrother. A novel NQO1 bioactivatable drug induces mitochondrial dysfunction and G2/M phase cell cycle arrest to selectively kill pancreatic cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6183.
Abstract 1628: Application of conditionally reprogrammed cell in cancer model establishment and new target identification
Authors: Yuan Long, Le Li, Shizhu Zhao, Song Xi, Danyi Wen
Journal: Cancer Research (2022)

Abstract Tumor cell immortalization through conditional reprogramming, particularly from limited biopsy specimen, is an invaluable tool to generate propagating tumor cells for cell-based drug sensitivity assay and bio-banking in vitro. We have successfully reprogrammed primary tumor cells from a number of tumor types, including lung carcinoma, breast cancer and glioma .etc. The conditionally reprogrammed cells exhibited typical colonized growth, which is well maintained upon cryopreservation. In some cases, the cells can be passaged for multiple times and likely become stable cell lines. We attempt to extend conditional reprogrammed tumor cells to reconstitute and grow PDX models in vivo and find the tumor formation rate is much higher than the primary tissue’s. This attempt provides a new process for establishing PDX models from variant types of cancer, especially the cancer types with low success rate in PDX establishment. We also establish PDX-derived cell lines by conditional reprogramming, which could be used in in vitro drug efficacy study and anti-cancer drug target identification. Functional library screening, such as genome-wide CRISPR/Cas9 library or specific pro-siRNA library screening, could discover new targets directly by evaluating the effect of the knockout/knockdown of specific genes. We have established several cell lines from drug resistant PDX, including Osimertinib and other targeted drugs resistant models, and found potential targets by pro-siRNA library screening. These potential targets could be validated on the matching cell line and PDX and the matching in vitro and in vivo tools will also enhance the further research of new targeted small molecules or antibodies. Citation Format: Yuan Long, Le Li, Shizhu Zhao, Song Xi, Danyi Wen. Application of conditionally reprogrammed cell in cancer model establishment and new target identification [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1628.
Abstract 3530: Microbial-Interleukin 17 receptor A (IL-17RA) signaling axis modulates tumor growth and microenvironment
Authors: Vidhi Chandra, Yu Zhang, Olivereen Le Roux, Joseph Petrosino, Jay Kolls, Florencia McAllister
Journal: Cancer Research (2022)

Abstract Microbiota, both within the gut and the tumors, has emerged as a significant player influencing tumor growth and responses to therapies. Recent evidence links microbiota and pancreatic ductal adenocarcinoma (PDAC), an aggressive cancer surrounded by a highly immuno-suppressive tumor microenvironment which limits efficacy of most available therapies. The immunosuppressive tumor microenvironment of PDAC is partially facilitated by a proinflammatory cytokine Interleukin 17 (IL-17). IL-17 can be stimulated by intestinal commensal bacteria under normal physiological conditions. It is critical for microbial defense as well as immunopathology. Both IL-17 neutralization and antibiotics reduce murine PDAC growth. While the vital role of microbiota in affecting tumor immunity has been identified, there is still a gap of knowledge as to how microbes may regulate pro-tumorigenic IL-17 signaling. We wanted to investigate the systemic and local role of IL-17 in regulating the microbial-tumor immune axis. For this purpose, we genetically deleted the IL-17 receptor A (IL-17RA) in different compartments and evaluated tumor growth. We found that IL-17RA signaling was important for maintaining microbial homeostasis and its disruption resulted in differential tumor growth. Absence of IL-17RA signaling in the gut lead to local inflammation as well as systemic immune effects. Our data suggests that modulation of IL-17 signaling could serve as a therapeutic intervention to alter microbial mediated tumor effects. The significance of these findings may extend to other cancers as well. Citation Format: Vidhi Chandra, Yu Zhang, Olivereen Le Roux, Joseph Petrosino, Jay Kolls, Florencia McAllister. Microbial-Interleukin 17 receptor A (IL-17RA) signaling axis modulates tumor growth and microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3530.
Abstract 1470: Characterization of ER receptor transcription complex using super resolution STORM microscopy
Authors: Tara Akhshi, Myles Brown
Journal: Cancer Research (2022)

Abstract Steroid/thyroid hormone receptors are ligand-dependent transcription factors (TFs) that play fundamental roles in cell development and homeostasis. They bind to their DNA response elements and modulate the transcription of target genes via interaction with co-regulators termed co-activators or co-repressors. Estrogen Receptor α (ERα) is an important member of this family which is expressed in in hormone receptor positive (ER+) breast cancer, one of the leading causes of death among women. Current therapeutic options involve endocrine therapies, however despite its effectiveness, a significant number of patients eventually experience resistance to these treatments, leading to disease recurrence and relapse. One of the major hurdles to combat resistant cells, is lack of comprehensive information about ERα transcriptional complex activity. While biochemical assays have provided significant information on interaction with its coregulators, it is not clear how the dynamic between these transpire. This is while ERα is a highly dynamic protein with a fast rate of interaction with coregulators and cycling between chromatin, nucleus, and cytosol. Consequently, it is critical to imply techniques that allow direct visualization of ERα activity and gain spatiotemporal information on its regulation. One of the major limitations to conduct such studies was due to the resolution limits inherited with light microscopes. However, the emerge of super resolution microscopes, offers a promising tool to overcome this challenge. Here, we imply super resolution microscopy to examine the mechanism of ERα transcriptional activity in the presence of estrogen as well as compounds that are currently used for endocrine therapy, Tamoxifen and Fulvestrant. We determine how each of these compounds influence ERα interaction with its co-activators (P300, SRC-3), and its co-inhibitor (NCoRI), and how these interactions modulate chromatin activity. Obtaining such information of ERα dynamics is critical to map the mechanism of its activity under different treatments, and thus is key to overcome some of the hurdles faced in endocrine therapy. Citation Format: Tara Akhshi, Myles Brown. Characterization of ER receptor transcription complex using super resolution STORM microscopy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1470.
Abstract 5566: Evaluation of the efficacy of ADC <i>in vitro</i> and <i>in vivo</i>
Authors: Jun Huang, Xiaohe Shi, Qingyang Gu, Qunsheng Ji
Journal: Cancer Research (2022)

Abstract Antibody drug conjugate (ADC) is a promising complex with therapeutic potential that aimed to the treatment of solid tumor and hematological malignancies. Compared with the therapeutic monoclonal antibody, ADCs-derived monoclonal antibody is conjugated with cytotoxic agents which can deliver potent cellular toxins to targeted cancer cells specifically. According to the specialization of ADCs, we have established the state-of-the-art platform to support the evaluation of the efficacy of ADC or the combination strategy of ADC and other anti-cancer therapy in the process of pre-clinical drug discovery. such as target validation, efficient internalization, cytotoxic effects and in vivo efficacy testing. In order to explore the mechanism of action and the functional effects of ADC for supporting the application of investigational new drug. Our flow cytometry platform (BD LSRFortessa X20) supports to evaluate the target validation and the process of internalization in a quick, reliable and reproducible way. Also we are able to construct customized antigen-specific overexpression or KI cells used for the development of ADCs which target on the specific antigens theoretically, for example, Claudin18.2 overexpressed MIA-PaCa-2 cell line. In terms of in vivo ADCs assessment, our abundant CDX and PDX resource facilitates the process of in vivo ADCs evaluation, and we have already assess the efficacy of ADC or the combination treatment of ADC and other anti-tumor drugs in several animal models. Last but not the least, our high-throughput MSD (MESO QuickPlex) and Luminex (Bio-Plex࣪ 200 system) platform boosts the evaluation of ADCs safety by measuring the extent of cytokine release syndrome. Citation Format: Jun Huang, Xiaohe Shi, Qingyang Gu, Qunsheng Ji. Evaluation of the efficacy of ADC in vitro and in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5566.
Abstract 821: Dissecting the role of Stag2 in lung adenocarcinoma
Authors: Emily L. Ashkin, Hongchen Cai, Yuning J. Tang, Chuan Li, Su Kit Chew, King Hung, Julia Belk, Saswati Karmakar, Jess Hebert, Maryam Yousefi, Charles Swanton, Dmitri A. Petrov, Monte Winslow
Journal: Cancer Research (2022)

Abstract Lung cancer is the most common cause of cancer-related deaths worldwide. Cancers are driven by genomic alterations that activate tumor-promoting oncogenes and inactivate tumor suppressor genes. While some of the most common driver genes have been extensively characterized, many tumor suppressor genes are less well studied. A better understanding of the mechanisms by which different tumor suppressor genes constrain tumorigenesis has the potential to uncover unappreciated biological processes that influence carcinogenesis. Recently, we performed an in vivo screen within a genetically engineered mouse model of oncogenic KRAS-driven lung cancer and found that STAG2 inactivation dramatically increases tumor growth. While STAG2 is mutated in ~4% of human lung adenocarcinomas, 20% of lung adenocarcinomas are low or negative for STAG2 protein. STAG2 is a subunit of one of the two major cohesin complexes, which are present in all cell types and have been implicated in many different cellular processes. STAG2 has not previously been recognized as a critical tumor suppressor in lung cancer and the mechanism through which its inactivation drives lung tumor growth is unknown. Immunohistochemistry, low-pass whole genome sequencing, and analysis of canonical target genes suggest that STAG2 inactivation is not associated with mechanisms previously implicated in other cancer types including chromosomal instability, increased DNA damage, or the activation of MEK/ERK or cGAS/STING signaling. Interesting, we have found that Stag2 is the only cohesin subunit that functions as a tumor suppressor in lung cancer in vivo. Chromatin accessibility profiling and gene expression analyses on Stag2-proficient and -deficient mouse lung adenocarcinoma cells have unveiled potential mediators and effects of STAG2 function. Ongoing genomic analyses of human and mouse lung cancers will demystify the relationship between major cohesin complexes, uncover the impact of STAG2 inactivation on cohesin binding genome wide, and investigate the role of Stag2 inactivation on the tumor microenvironment. We anticipate that our study will uncover the mechanisms of STAG2-mediated tumor suppression in lung cancer and provide novel insights into lung tumorigenesis. Citation Format: Emily L. Ashkin, Hongchen Cai, Yuning J. Tang, Chuan Li, Su Kit Chew, King Hung, Julia Belk, Saswati Karmakar, Jess Hebert, Maryam Yousefi, Charles Swanton, Dmitri A. Petrov, Monte Winslow. Dissecting the role of Stag2 in lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 821.
Abstract 1429: DDT induces intergenerational epigenetic inheritance of cancer predisposition in a mouse model
Authors: Raquel Santana Da Cruz, Odalys Dominguez, Apsra Nasir, Alexandra K. Gonsiewski, Maria Idalia Cruz, Lu Jin, Matthew McCoy, Sonia de Assis
Journal: Cancer Research (2022)

Abstract DNA sequence accounts for the majority of disease heritability, including cancer. Yet, not all familial cancer cases can be explained by genetic factors. There is mounting evidence that environmentally-induced epigenetic inheritance occurs and that the progeny’s traits can be shaped by parental environmental experiences. In humans, epidemiologic studies have implicated endocrine disruptors and environmental toxicants such as the pesticide DDT in intergenerational cancer development, including breast and childhood tumors. Using a mouse model, we investigated whether paternal DDT exposure may result in an intergenerational increase in breast cancer development. We also investigated the effects of DDT on the paternal germline and the mechanisms underlying intergenerational transmission. Male mice (c57bl/6) were exposed to DDT or to a control-vehicle (CO) solution and used for sperm collection or mating with unexposed females to produce the DDT or CO daughters. In another experiment, normal mouse embryos (zygote stage) were injected with RNA purified from sperm of DDT or CO males or miRNA mimic. Resulting zygotes were implanted into surrogate mothers to produce offspring. DDT daughters or RNA injected females were used to study breast cancer development (carcinogen-induced or orthotopic models). We found that the female progeny of males exposed to DDT in the pre-conception period have higher susceptibility of developing aggressive tumors in two different mouse models of breast cancer. Sperm of DDT-exposed males exhibited distinct patterns of small non-coding RNAs, with an increase in miRNAs and a specific surge in miRNA-10b levels. Remarkably, embryonic injection of the entire sperm RNA load of DDT-exposed males or synthetic miRNA-10b recapitulated the tumor phenotypes observed in DDT daughters. We also found that E3.5 embryos injected with miR-10b have altered transcriptional profile compared to controls. Our findings reveal a causal role for sperm RNAs in the inheritance of cancer predisposition and could explain some of the “missing heritability” of breast and other malignancies, if confirmed in humans. Citation Format: Raquel Santana Da Cruz, Odalys Dominguez, Apsra Nasir, Alexandra K. Gonsiewski, Maria Idalia Cruz, Lu Jin, Matthew McCoy, Sonia de Assis. DDT induces intergenerational epigenetic inheritance of cancer predisposition in a mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1429.
Abstract 2134: Discovery and structure activity relationships of BAY 2666605: PDE3A-SLFN12 complex inducer for cancer therapy
Authors: Stefan Gradl
Journal: Cancer Research (2022)

Abstract Velcrin compounds are small molecules which act as molecular glues to form a PDE3A-SLFN12 complex. This complex formation induces apoptosis in cancer cells expressing elevated levels of PDE3A and SLFN12 (de Waal et al., Nat Chem Biol 2016; Wu et al., J Bio Chem 2020). Unlike traditional targeted therapies that leverage dependencies created by genomic alterations in cancer cells, velcrins instead kill cancer cells by a gain-of-function mechanism dependent on stimulation of SLFN12 RNase activity by complex formation with PDE3A (Garvie et al., Nat Commun 2021). Based on in-vivo tool compounds which were discovered by hit-to-lead optimization from a phenotypic screen (Lewis et al., ACS Med Chem Lett 2019), the team set out to optimize the properties of the tool compounds. While already showing excellent potency and in-vivo efficacy in various tumor models, the compounds were only approximately tenfold selective against PDE3A when compared to their cell killing activity. PDE3A/B activity most notably influences cardiohemodynamics and inhibition of PDE3A/B was to be reduced to generate a larger safety window. Co-crystallization of analogs with PDE3A showed the binding mode of the velcrin class and changes in the solvent exposed region of the PDE3A binders led to steep activity changes in complex formation and cell killing. Careful optimization of the ratio of cell killing to PDE3A activity while optimizing DMPK and safety pharmacology led to the discovery of BAY 2666605. BAY 2666605 has recently entered a First-in-Human study (NCT04809805) in patients with advanced solid tumors that co-express PDE3A and SLFN12, including melanoma, ovarian cancer, and sarcoma. We will discuss the discovery and structure activity relationships of BAY 2666605. Citation Format: Stefan Gradl. Discovery and structure activity relationships of BAY 2666605: PDE3A-SLFN12 complex inducer for cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2134.
Abstract 782: Multiomic single cell sequencing identified regulatory elements in prostate cells
Authors: Yijun Tian, Alex Soupir, Liang Wang
Journal: Cancer Research (2022)

Abstract Introduction: Despite significant progress, the genetic role of regulatory elements in gene expression is still poorly understood in prostate cells. Recent development in single cell sequencing by combining ATAC-seq and RNA-seq has made it possible to determine genome-wide linkages between chromatin accessibilities and gene expression. Methods: To test the feasibility of using single cell multiome sequencing in dissecting regulatory linkages between chromatin accessibilities and gene expressions, we applied 10X Genomics Chromium Single Cell Multiome ATAC + Gene Expression platform to simultaneously encapsulate Tn5 transposase tagged nuclei from two prostate cell lines. We applied down-sampling linkage analysis to determine highly reproducible genome-wide associations between ATAC-seq peaks and RNA-seq gene expressions. To investigate the chromatin accessibilities related to human transcription factor binding sites, we scanned the JASPAR motif collection with genome-wide Tn5 insertion analysis. Results: This study encapsulated 3,096 multiome RWPE-1 nuclei cultured in serum-free condition, 6,978 and 8,487 multiome LNCaP nuclei treated with methanol (LNCaP-M) or dihydrotestosterone (DHT, LNCaP-D). Our analysis captured 210,990, 264,802, and 278,154 ATAC-seq peaks from RWPE-1, LNCaP-M, and LNCaP-D by macs2 narrow peak model (FDR q&amp;lt;0.01), which included over 90% peaks identified by bulk ATAC-seq datasets. Through downsampling linkage analysis, we identified 1,595, 2,507, and 4,183 linkage associations between ATAC-seq and RNA-seq from the above three experiments, respectively. Scatter plots showed that the correlation coefficient of the linkage association was negatively associated with the distance between ATAC-seq and RNA-seq signals. By comparing to bulk ChIP-seq data from RWPE-1 cells, we confirmed that the single cell ATAC-seq peaks in linkages were co-localized at histone modified regions, including H3K4me1 (25.7%), H3K27ac (14.3%), and H3K4me3 (4.9%). JASPAR database (634 motifs) search found that the Tn5 footprints surrounding AR, NR3C1, and NR3C2 motifs in LNCaP-D showed significantly higher enrichment than that of the LNCaP-M group, indicating increased androgen receptor DNA binding following DHT treatment. Interestingly, in RWPE-1 cells harboring TP53 p.P72R polymorphism (rs1042522), we found differential Tn5 footprints surrounding TP53 binding motif between its ATAC-seq subclusters at whole genome scale. Conclusion: Our preliminary data in prostate cell lines outlined a regulatory landscape of single-cell resolution. Multiomic single cell sequencing will help locate regulatory elements and target genes. Citation Format: Yijun Tian, Alex Soupir, Liang Wang. Multiomic single cell sequencing identified regulatory elements in prostate cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 782.
Small intestinal resident eosinophils maintain gut homeostasis following microbial colonization
Authors: Aline Ignacio, Kathleen Shah, Jeremiah Bernier-Latmani, Yasmin Köller, Gillian Coakley, Mati Moyat, Romain Hamelin, Florence Armand, Nick C. Wong, Hena Ramay, Carolyn A. Thomson, Regula Burkhard, Haozhe Wang, Antoine Dufour, Markus B. Geuking, Braedon McDonald, Tatiana V. Petrova, Nicola L. Harris, Kathy D. McCoy
Journal: Immunity (2022)